Habits are powerful in driving actions. In substance abuse, habits formed by repeated hedonic experience with a drug are more powerful than explicit knowledge of the drug's detrimental effects. Recent research in the cognitive neuroscience of learning and memory has greatly advanced our understanding of these two forms of learning, suggesting they depend on distinct neural systems. Yet there has been remarkably little progress in extending this line of research to the study of addiction. Here, we propose to bridge this gap to understand the neural mechanisms contributing to different forms of learning and motivation, and their disruption in addiction. Research demonstrates that habit learning depends on the striatum and its dopaminergic inputs, while explicit memory for facts and events, often referred to as declarative memory, depends on the medial temporal lobe (MTL;hippocampus and surrounding cortices). Recent evidence suggests these systems may interact competitively under some circumstances. The core hypothesis motivating this proposal is that substance abuse may be related to a disrupted balance between these two learning systems and the extent to which each of them guides behavior. The proposed research will use functional imaging (fMRI) and behavioral analyses to investigate how different forms of learning guide decisions and actions. The central aim is to understand how to modulate the contribution of these two learning systems to choice behavior, at both the neural and behavioral levels. In the first study, we will examine the effects of modulating striatal contributions to learning and choice. To that end, we will manipulate reinforcement, and will determine the effects on the cognitive and neural systems driving subsequent choice behavior (Expt 1). In the second study, we will examine the effects of modulating MTL contributions to learning and choice. To that end, we will manipulate stimulus and associative novelty, and will determine the effects on the cognitive and neural systems driving subsequent choice behavior (Expt 2). Determining factors that modulate the extent to which learning and choice depend on one system or the other will lay the foundation for future translational work on potential treatment interventions that can reduce the dependence of behavior on the striatal habit system in favor of the MTL declarative system. PUBLIC HEALTH RELEVANCE: Substance abuse is a serious problem of public health. Disruption to the brain and cognitive mechanisms underlying learning are central to the pathology of substance abuse and addiction. In substance abuse, individuals'behavior is driven by habits that are learned as a result of repeated experiences with the drug's hedonic, reinforcing effects. These learned habits override any other forms of learning, such as explicit knowledge or experiences of the drugs'detrimental effects. The proposed studies aim to understand the neural and cognitive mechanisms underlying the balance between habitual and explicit forms of learning, and how this balance can be modified. The resulting knowledge will inform future work on potential cognitive and pharmacological treatment strategies that can reduce the dependence of behavior on habits in favor of explicit, goal-directed mechanisms.